Fibroblast growth factor homologous factors (FHFs) are intracellular neuromodulators whose mechanisms of action are still poorly understood. Mice bearing deletions in Fhf genes display neurological deficits associated with motor[unreadable] function, although the animals show no detectable histological or immunohistochemical abnormalities. FHFs are[unreadable] believed to exert their effects through identified binding partners, which include voltage-gated sodium channels.[unreadable] Recent findings from the P.I.'s lab show that FHFs are required for proper intrinsic excitability of neurons, and that[unreadable] FHF-deficient neurons show aberrant voltage-dependent sodium channel behavior. Further data show that FHFs are[unreadable] required for optimal conduction of action potentials along motor axons. In light of these findings, this application[unreadable] proposes experiments to answer four related questions concerning FHF physiology:[unreadable] I. Do FHFs modulate neuronal excitability through direct FHF-sodium channel interactions?[unreadable] II. Are different FHF genes and protein isoforms equivalent or distinct in terms of sodium channel modulation and[unreadable] excitability?[unreadable] III. Does temporal regulation of FHF protein levels contribute to plasticity of intrinsic excitability?[unreadable] IV. Do FHF protein levels impact on the functional severity of demyelination syndromes?[unreadable] These experiments are expected to more fully define the mechanisms and conditions by which FHFs control physiology[unreadable] and pathophysiology of the central nervous system. More specifically, these studies will analyze FHF genes as[unreadable] potential contributors to severity of Charcot-Marie-Tooth syndrome and diabetic peripheral neuropathy, the latter of[unreadable] which constitutes a significant minority health disparity.